title: IGHV unmutated CLL B cells are more prone to spontaneous apoptosis and subject to environmental prosurvival signals than mutated CLL B cells.
abstract: Tumor cells in chronic lymphocytic leukemia (CLL) are more prone to apoptosis when cultured ex vivo, because they lack prosurvival signals furnished in vivo via B-cell receptor (BCR)-dependent and -independent pathways. This study compared the susceptibility of unmutated (UM) and mutated (M) CLL B cells to spontaneous apoptosis and prosurvival signals. UM CLL B cells showed a significantly higher rate of spontaneous apoptosis than M CLL B cells. Nuclear factor-kB (NF-kB) was rapidly inactivated, and B-cell leukemia/lymphoma 2 (Bcl-2) expression progressively down-regulated in the UM CLL B cells. CD40-Ligand, interleukin-4 and stromal cells significantly improved their viability and partially recovered Bcl-2, but not NF-kB expression. Peripheral blood mononuclear cells also offered protection of UM CLL B cells, and recovered both NF-kB and Bcl-2 expression. T cells, rather than nurse-like cells, were responsible for protecting UM CLL B cells by means of cell-to-cell contact and soluble factors. Despite their more aggressive features, UM CLL B cells are more susceptible to spontaneous apoptosis and depend from environmental prosurvival signals. This vulnerability of UM CLL B cells can be exploited as a selective target of therapeutic interventions.
authors.affiliation: Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliero Universitaria San Giovanni Battista di Torino, Torino, Italy. marta.coscia@unito.it
authors.forename: M
authors.initials: M
authors.lastname: Coscia
authors.forename: F
authors.initials: F
authors.lastname: Pantaleoni
authors.forename: C
authors.initials: C
authors.lastname: Riganti
authors.forename: C
authors.initials: C
authors.lastname: Vitale
authors.forename: M
authors.initials: M
authors.lastname: Rigoni
authors.forename: S
authors.initials: S
authors.lastname: Peola
authors.forename: B
authors.initials: B
authors.lastname: Castella
authors.forename: M
authors.initials: M
authors.lastname: Foglietta
authors.forename: V
authors.initials: V
authors.lastname: Griggio
authors.forename: D
authors.initials: D
authors.lastname: Drandi
authors.forename: M
authors.initials: M
authors.lastname: Ladetto
authors.forename: A
authors.initials: A
authors.lastname: Bosia
authors.forename: M
authors.initials: M
authors.lastname: Boccadoro
authors.forename: M
authors.initials: M
authors.lastname: Massaia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D023201:CD40 Ligand / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand